First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors

Abstract

Purpose: OX40, a receptor transiently expressed by T cells upon antigen recognition, is associated with co-stimulation of effector T cells and impairment of regulatory T cell function. This first-in-human study evaluated MOXR0916, a humanized effector-competent agonist IgG1 monoclonal anti-OX40 antibody. Patients and Methods: Eligible patients with locally advanced or metastatic refractory solid tumors were treated with MOXR0916 intravenously once every 3 weeks (Q3W). A 3+3 dose-escalation stage (0.2-1200 mg) (n=34) was followed by expansion cohorts at 300 mg (n=138) for patients with melanoma, renal cell carcinoma, non-small cell lung carcinoma, urothelial carcinoma, and triple-negative breast cancer. Results: MOXR0916 was well tolerated with no dose-limiting toxicities observed. A maximum tolerated dose was not reached. Most patients (95%) experienced at least one adverse event (AE); 56% of AEs, mostly grade 1-2, were related to MOXR0916. Most common treatment-related AEs included fatigue (17%), diarrhea (8%), myalgia (7%), nausea (6%), decreased appetite (6%), and infusion-related reaction (5%). Pharmacokinetic parameters were dose proportional between 80–1200 mg and supported Q3W administration. The recommended expansion dose based on pharmacokinetics and OX40 receptor saturation was 300 mg Q3W. Immune activation and upregulation of PD-L1 was observed in a subset of paired tumor biopsies. One renal cell carcinoma patient experienced a confirmed partial response. Overall, 33% patients achieved stable disease. Conclusions: Although objective responses were rarely observed with MOXR0916 monotherapy, the favorable safety profile and evidence of tumor immune activation in a subset of patients support further investigation in combination with complementary agents such as PD/PD-L1 antagonists.

First-in-human phase I study of the OX40 agonist GSK3174998 with or without pembrolizumab in patients with selected advanced solid tumors (ENGAGE-1)

“…median pharmacokinetic profiles at dose levels ≥0.3 mg/ kg GSK3174998 exposure appeared to be dose proportional with two-compartment behavior expected for mAbs and with target-mediated clearance apparent at lower doses, similar to data reported for another OX40 agonist, MOXR0916. 32 While pharmacodynamic effects were observed in the peripheral blood, including upregulation of some inflammatory cytokines, none were dose related. No confirmed response was observed for GSK3174998 monotherapy.…”

Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response

“… 207 Mouse models have shown that specific antibodies that stimulate OX40 can reduce the number of Tregs, thereby maintaining the function of effector T cells and showing high antitumor activity. 208 – 210 …”

The combination of oxaliplatin and anti-PD-1 inhibitor promotes immune cells infiltration and enhances anti-tumor effect of PD-1 blockade in bladder cancer

“…CD134 (also known as OX40) is a co-stimulatory receptor that is predominantly expressed on activated T cells to regulate the division and survival of conventional T cells ( 31 ). Activating CD134 changes tumor immune activation and promotes the efficiency of ICIs ( 32 , 33 ). The anti-CD134 agonist antibodies increased CD4 + T cells in pancreatic cancer mouse models and have a synergistic effect with anti-PD-1 inhibitor to eradicating tumor ( 34 ).…”